Carbohydrates are playing an increasingly important part in biochemical research and in development of new pharmaceutical therapies, because carbohydrates are involved in a myriad of biological functions, including cellular recognition, signaling, and even the development of disease states.[1-4] Having access to consistent, pure and inexpensive carbohydrate starting materials is an important factor in the continuation of this research. This access is vitally important if the carbohydrate is not readily available from inexpensive sources, such as L-sugars and other rare sugars. Such sugars can only be used as starting materials for new biochemical and pharmaceutical compounds If their supply is not limited. The demand for the rare sugar L-ribose is increasing, because L-ribose is a starting material for many L-nucleoside-based pharmaceutical compounds. L-Nucleoside-based drugs have shown antiviral, antimalarial, and anticancer activities.[5] These nucleosides target many different viruses including HIV, hepatitis B (HBV), and Epstein-Barr.[6] The first nucleoside-based pharmaceutical therapy was (±)-2,3-dideoxy-3′-thiacytidine (BCH-189), displaying anti-HIV activity. To the surprise of many researchers, the L-form (L-3TC) was more potent and less toxic than the more “natural” D-form of BCH-189.[5] The interest in L-nucleosides has increased as noted in Table 1 showing several L-nucleoside-based pharmaceutical compounds presently in clinical trials. Many of these nucleoside-based drugs can be prepared from L-ribose, including Epivir, Elvucitabine, Clevudine, Telbivudine, and val-LdC.[7-9]
TABLE 1Current L-nucleoside based pharmaceuticals currently approved by theUnited States Food and Drug Administration or undergoing clinical trials.Trade nameGeneric NameCompanyConditionStatus (US)EPIVIR ®3TC (lamivudine)GSKHIVapprovedElvucitabineL-Fd4C (ACH-AchillionHIV, HBVPhase II126,443)EmtricitabineFTCGileadHIV, HBVapprovedClevudineL-FMAUBukwangHBVPhase IIIPentaceptL-3′-FD4CPharmassetHBVTelbivudineL-dTIdenixHBVPhase IIIPharmaceuticalsn/aval-LdCIdenixHBVPhase IIbPharmaceuticalstroxacitabineTROXATYL ®,BioChem Pharma Incsolid tumorsPhase IIBCH-4556n/aL-d4NIdenixHBVPharmaceuticals
The need for inexpensive sources of L-ribose for the synthesis of L-nucleoside-based drugs is specifically seen in the synthesis of the nucleoside-based pharmaceutical drug 2′-deoxy-2′-fluoro-5-methyl-b-L-arabinofuranosyl uracil (L-FMAU). Chu and coworkers synthesized L-FMAU from L-arabinose.[10] However, their first synthetic step converted the L-arabinose to L-ribose. This step was needed because L-ribose is more expensive and less readily available than L-arabinose. By providing an inexpensive source of L-ribose, medicinal chemists can produce these and other drugs with fewer synthetic steps, decreased time, and increased yields that ultimately generate lower costs for researchers and patients.
The need for less expensive sources of L-ribose has become apparent from the dramatic increase in prices. A current bulk pricing for L-ribose is approximately $2500 per kg, up from the $700 to $1000 per kg seen quoted two years ago.[11] With the steady increase in anti-HIV and anti-HCV pharmaceutical candidates based on L-ribose currently undergoing clinical trials, prices for the L-ribose will surely continue to increase. Thus, dramatically increasing the costs of these life-saving drugs and pricing themselves out of reach for the HIV and HCV infected people in poor countries.
Currently, several companies are exploring synthetic routes for producing L-ribose. Each of these routes has their own limitations. Both Danisco and BioRefining produce L-ribose from L-arabinose extracted from natural sources, such as biomass, which requires extensive and expensive purification technologies.[12] The conversion of L-arabinose to L-ribose utilizes xylose isomerase.[13] This conversion is not very efficient, and therefore requires additional purification, further increasing costs.[13] HanChem uses a chemical process to convert D-mannose to L-ribose. This process uses a piperidine inversion of D-manno-1,4-lactone as the key synthetic step.[14] The second-generation process requires 8 synthetic steps and does not produce a high yield of L-ribose.[14] This route may become less commercially viable due to the increased cost of D-mannose.[11] Even if an inexpensive source of D-mannose were secured for this process, this eight-step synthesis would be too costly to create an inexpensive source of L-ribose. API has a fermentative route to L-ribose from D-glucose.[15] This route uses a Trichosporonoides strain, a Gluconobacter strain, and a Cellulomonas strain in separate fermentations to convert D-glucose to L-ribose.[15] While D-glucose is an inexpensive starting material, the cost of the three-step sequential and separate fermentations is cost prohibitive.